Input-specific control of reward and aversion in the ventral tegmental area

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Ventral tegmental area (VTA) dopamine neurons have important roles in adaptive and pathological brain functions related to reward and motivation. However, it is unknown whether subpopulations of VTA dopamine neurons participate in distinct circuits that encode different motivational signatures, and whether inputs to the VTA differentially modulate such circuits. Here we show that, because of differences in synaptic connectivity, activation of inputs to the VTA from the laterodorsal tegmentum and the lateral habenula elicit reward and aversion in mice, respectively. Laterodorsal tegmentum neurons preferentially synapse on dopamine neurons projecting to the nucleus accumbens lateral shell, whereas lateral habenula neurons synapse primarily on dopamine neurons projecting to the medial prefrontal cortex as well as on GABAergic (γ-aminobutyric-acid-containing) neurons in the rostromedial tegmental nucleus. These results establish that distinct VTA circuits generate reward and aversion, and thereby provide a new framework for understanding the circuit basis of adaptive and pathological motivated behaviours.

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Figure 1: LDT and LHb preferentially project to distinct VTA subregions.
Figure 2: Stimulation of LDT and LHb inputs to the VTA elicits CPP and CPA.
Figure 3: LDT neurons preferentially synapse on dopamine neurons projecting to the NAc lateral shell.
Figure 4: LHb neurons preferentially synapse on dopamine neurons projecting to the mPFC and RMTg GABAergic neurons.
Figure 5: Rabies virus reveals distinct VTA circuits and effects of dopamine receptor antagonists on CPP and CPA.


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We thank the Stanford Neuroscience Imaging Core, the Stanford Neuroscience Behavior Phenotyping and Pharmacology Core and the Stanford Neuroscience Gene Vector and Virus Core (all supported by National Institutes of Health grant NIH NS069375). This work was supported by grants from the Simons Foundation and NIH (to R.C.M.). K.D. is supported by the NIH, the DARPA REPAIR program, and the Wiegers Family Fund. S.L. is supported by a fellowship from the German Academy of Sciences Leopoldina. B.K.L. is supported by a Davis Foundation Postdoctoral Fellowship in Eating Disorders Research. K.M.T. is supported by the JPB Foundation and NIMH.

Author information

S.L., B.K.L. and R.C.M. designed the study, interpreted results and wrote the paper. S.L. and B.K.L. performed stereotactic injections, optogenetic experiments and electrophysiology. S.L., C.R., M.J.B. and K.W.H. performed immunohistochemistry. B.K.L. and K.W.H. generated viruses. K.T. and K.D. provided optogenetics training and resources. All authors edited the paper.

Correspondence to Robert C. Malenka.

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Lammel, S., Lim, B., Ran, C. et al. Input-specific control of reward and aversion in the ventral tegmental area. Nature 491, 212–217 (2012) doi:10.1038/nature11527

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